HCV-related lymphoproliferative disorders in the direct-acting antiviral era: From mixed cryoglobulinaemia to B-cell lymphoma

Abstract

Hepatitis C virus (HCV) has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes are specialized in producing immunoglobulins, and within chronic HCV infection they can cause a range that goes from polyclonal hypergammaglobulinemia without clinical repercussions, passing by mixed cryoglobulinemic vasculitis and eventually reaching B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the last steps towards overt malignancy. This has direct implications in treatment strategies, which always include the use of direct-acting antiviral agents sometimes associated with immunosuppressants. The role of direct-acting antiviral agents has been well established in patients with cryoglobulinemia vasculitis. Its positive impact on B cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.

CLEC18A Impairs Phagocytosis by Reducing FcγRIIA Expression and Arresting Autophagosome-Lysosome Fusion

“…The recent advent of direct-acting antivirals (DAAs) has achieved remarkable therapeutic efficacy in HCV patients ( 14 ). We analyzed the dynamics of the HCV titer, cryoglobulin concentration, and CLEC18A expression in the sera of HCV-MC patients receiving DAAs therapy.…”

Cryoglobulinemic vasculitis: a 2023 update

“…Stimulated atypical memory B cells also secrete IgMs with rheumatoid factor [18]. In addition, TLR signaling on atypical memory B cells stimulates the secretion of Th1 cytokines such as tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-g), thus promoting proliferation and activation of effector Th1 cells [19,11].…”

“…These factors could be used to predict CV response after DAAs therapy and to define personalized follow-up strategies. Whether DAAs may have a positive impact on B-NHL needs to be confirmed in larger studies with longer follow-up [11].…”

“…Overall, when considering CV disease severity, MC can be classified into three categories: non-severe, severe, and life-threatening disease. Finally, CV patients display a higher risk for all B-non Hodgkin lymphomas (B-NHL subtypes) with the strongest associations being described with low-grade marginal zone lymphoma (MZL) occurring in the spleen or liver, lymphoplasmacytic lymphoma, and with high-grade diffuse large B-cell lymphoma (DLBCL) [11]. Laboratory analysis often shows low C4 serum complement fraction, decreased CH50 and high levels of rheumatoid factor [8].…”

“…In both scenarios, however, the lymphoproliferative continuum explains the similar possible shift from low-grade to high-grade lymphomas that has been described in all the disease subgroups and that is fostered by cytokines, mutations in proto-oncogenes and tumor suppressor genes, oxidative stress and dysregulation in intracellular networks. Finally, both in HCV-related and HCV-negative CV, high-grade lymphomas can also occur de novo, without necessarily passing through the low-grade B-NHL stage [11].…”